title: Intrathecal P/Q- and R-type calcium channel blockade of spinal substance P release and c-Fos expression.
abstract: Intrathecal (IT) studies have shown that several voltage sensitive calcium channels (VSCCs), such as the L-, N- and T-type may play roles in nociception and that of these only the N-type regulates primary afferent substance P (SP) release. However, the actions of other VSCCs at the spinal level are not well known. We investigated the roles of spinal P/Q- and R-type VSCCs, by IT administration of R-type (SNX-482) and P/Q-type (ω-agatoxin IVA) VSCC blockers on intraplantar formalin-evoked flinching, SP release from primary afferents and c-Fos expression in spinal dorsal horn. Intraplantar injection of formalin (2.5%, 50 μL) produced an intense, characteristic biphasic paw flinching response. In rats with IT catheters, IT SNX-482 (0.5 μg) reduced formalin-evoked paw flinching in both phase 1 and 2 compared with vehicle. Intraplantar formalin caused robust neurokinin 1 receptor (NK1r) internalization (indicating SP release) and c-Fos expression in the ipsilateral dorsal horn, which were blocked by IT SNX-482. IT ω-agatoxin IVA (0.03, 0.125 and 0.5 μg) did not reduce formalin-evoked paw flinching or c-Fos expression at any doses, with higher doses resulting in motor dysfunction. Thus, we demonstrated that blockade of spinal R-type, but not P/Q type VSCCs attenuated formalin-induced pain behavior, NK1r internalization and c-Fos expression in the superficial dorsal horn. This study supports a role for Cav2.3 in presynaptic neurotransmitter release from peptidergic nociceptive afferents and pain behaviors.
authors.affiliation: Department of Anesthesiology, Dokkyo Medical University, School of Medicine, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan; Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, San Diego, La Jolla, CA 92093-0818, USA. Electronic address: youtei3@gmail.com.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Terashima
authors.affiliation: Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, San Diego, La Jolla, CA 92093-0818, USA. Electronic address: q1xu@ucsd.edu.
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Dokkyo Medical University, School of Medicine, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan. Electronic address: shigeki@dokkyomed.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, San Diego, La Jolla, CA 92093-0818, USA. Electronic address: tyaksh@ucsd.edu.
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008297:Male; D009069:Movement Disorders / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D014110:Touch / Q000187:drug effects / Q000502:physiology; D014828:Vocalization, Animal / Q000187:drug effects; D020867:omega-Agatoxin IVA / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D016760:Proto-Oncogene Proteins c-fos; D018040:Receptors, Neurokinin-1; C115521:SNX 482; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; D013373:Substance P; D010751:Phosphopyruvate Hydratase
keywords: CGRP; DRG; G protein-coupled receptor; GPCR; IB4; IR; IT; N-methyl-d-aspartate; NK1r; NMDA; Neurokinin 1 receptor; SNX-482; SP; Spinal cord; TRPV1; VSCCs; Voltage sensitive calcium channels; c-Fos; calcitonin gene-related peptide; dorsal root ganglia; immunoreactive; intrathecal; isolectin B4; neurokinin 1 receptor; substance P; transient receptor potential protein vanilloid 1; trkA; tropomyosin receptor kinase A; voltage-sensitive calcium channels; ω-Agatoxin IVA